The antigenic drift of viral glycoproteins must be balanced by purifying selection pressure to maintain functionality. Understanding these evolutionary processes is key to predicting and combating viral evolution but is primarily based on influenza A(H3N2), which may limit generalisability. By characterising the influenza B virus haemagglutinin (HA) over 8 decades of circulation in humans, we found continuous genetic diversification, punctuated with antigenic changes that did not follow a linear path in antigenic space. Antigenic change is primarily underpinned by re-occurring mutations and deletions at positions 136, 150, 162-165, 197 and 203. These residues form complex epistatic networks that modulate the antigenic impact of mutation recycling. They also generate permissive backbones on which immune escape can emerge with limited replicative fitness cost. Our study identifies critical similarities and differences with A(H3N2) evolution and demonstrates the role of epistasis in balancing antigenic novelty with viral fitness. Our findings and genetic, antigenic and phenotypic datasets support the development of genotype-to-phenotype prediction tools, but such predictions need to capture the complex outcomes of epistasis.
Lara S. U. Schwab, Ruo-Peng Xie, Ellie Reilly et al.· bioRxiv· 0 citations
ABSTRACT Lipid nanoparticles (LNPs) have rapidly emerged as the leading delivery platform for nucleic acid therapeutics due to their high encapsulation efficiency, scalable manufacturing, and clinical success in siRNA and mRNA medicines. Poly(ethylene glycol)‐lipids ((PEG)–lipids) have been central to this progress by providing steric stabilization, size control, and tunable biodistribution. However, PEGylation also introduces important limitations, including complement activation, pre‐existing and treatment‐induced anti‐PEG antibodies, and accelerated blood clearance, which increasingly constrain repeated and long‐term dosing strategies. This review focuses on recent advances in PEG‐alternative LNP designs, including non‐PEG polymers, zwitterionic and biomimetic lipids, polypeptides, and structurally modified PEG analogues. We compare how polymer chemistry, anchor geometry, and grafting architecture influence LNP formation, physicochemical properties, biodistribution, cellular uptake, and immunological outcomes. Moreover, we discuss key challenges that remain in translating PEG‐free and PEG‐modified LNPs toward clinical application and propose future directions to better understand in vivo behavior and enable rational design of next‐generation stealth LNPs. Overall, PEG lipid alternatives should not be viewed as simple PEG mimics, but as distinct surface‐engineering materials that create new nano‐bio interfaces and reshape LNP behavior in biological systems.
Zihnil A I Mazrad, Yi Ju, S. J. Kent et al.· Advancement of science· 0 citations
We use cookies to run the site and, with your consent, for analytics and to show ads.
See our Cookie Policy.
